A significant inherited susceptibility locus for non-insulin dependent diabetes (NIDDM) is suggested by a high concordance in identical twins, strong familial aggregation, and evidence from segreagation analysis for a major gene for both the disease and intermediate phenotypes. Despite extensive study, no predisposing biochemical defect has been identified conclusively. Known loci explain <1% of inherited diabetes. The positional search strategy offers a powerful alternative approach to identify diabetes susceptibility genes and to understand the early stages of NIDDM pathophysiology. We hypothesize that NIDDM susceptibility is determined by a locus with major clinical impact in an oligogenic disease model, and that this locus will result in an identifiable phenotypic subgroup of pedigrees with a strong family history of NIDDM onset before age 65.